The trans-syn class of marine polyether natural products produced by marine dinoflagellates are some of the most potent non-macromolecular biologicals known. Brevetoxins (PbTxs) and ciguatoxins (CTXs) are well known as the only ligands known to bind to site 5 on voltage-gated sodium channels (VGSCs) with high affinity. In 2004, we discovered brevenal, a third class of polyether ion channel modulator which counteracts the effects of site 5 toxic ligands. Unlike brevetoxins and ciguatoxins which are toxic in the nanomolar to picomolar concentration ranges, brevenal is non-toxic as far as we have investigated. More importantly, brevenal is an antagonist which negates, reduces, or prevents the effects of brevetoxin and ciguatoxin in every system examined. Receptor binding studies have demonstrated that brevenal does not directly compete for site 5 but non-competitively regulates PbTx activity. Biological testing showed brevenal to be antagonistic to the toxic effects of brevetoxins and ciguatoxins in vivo. In sheep inhalation models, brevenal blocks PbTx-induced bronchoconstriction and leads to increased tracheal mucous velocity. Implications for treatment of neurotoxic shellfish poisoning (NSP due to brevetoxin) and ciguatera fish poisoning (CFP due to ciguatoxin), or more broadly for the treatment of asthma, COPD or Cystic Fibrosis are supported through experimental results. In short, brevenal is a molecular class worthy of study. Key objectives of this proposal are to produce semi-synthetic brevenal derivatives that a) exhibit increased affinity (<10 nM) and retention of receptor selectivity for the brevenal receptor, ultimately enabling the isolation and characterization of this novel receptor, and b) assess synthetically-produced derivative brevenal ligands which exhibit improved efficacy against the effects of brevetoxin and ciguatoxin in in vito models. The ultimate goal of this research is to identify polyether brevenal derivatives with potential for use in the treatment ion-channel mediated disorders, with specific intent towards NSP and CFP, and for those naturally occurring human maladies like asthma, COPD, and cystic fibrosis, for which there is a demonstrated ion channel mediation/dysfunction. By analogy, the brevenal receptor site which will become more fully characterized as a result of this application provides a new drug locus for therapeutic ligand development. PDF created with pdfFactory trial version www.pdffactory.com PUBLIC HEALTH RELEVANCE: Ingestion or inhalation of the marine polyether compounds, brevetoxins or ciguatoxins, can lead to respiratory difficulty and prolonged neurological disorders for which there is, currently, no known treatment or cure. Brevenal, a natural product derived from the marine dinoflagellate Karenia Brevis has been shown to block effects of brevetoxins and ciguatoxins. Synthesis of highly potent brevenal derivatives could lead to compounds with the potential for treating exposure to environmental neurotoxins and aid in the identification of a new drug locus for treatment of pulmonary disorders such as asthma, cystic fibrosis and COPD. PDF created with pdfFactory trial version www.pdffactory.com